Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy: A Phase 2b Randomized Clinical Trial.

Importance: Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics. Objective: To evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs). Design, Setting, and Participants: This phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe. Interventions: Patients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose). Main Outcomes and Measures: The primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted. Results: A total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% (P < .001 vs placebo; IQR, -80.4% to -16.9%) for 25 mg, 46.4% (P < .001 vs placebo; IQR, -76.7% to -14.0%) for 20 mg, and 33.2% (P = .04 vs placebo; IQR, -61.8% to 0.0%) for 10 mg, compared with 18.2% (IQR, -37.3% to 7.0%) for placebo. XEN1101 was generally well tolerated and TEAEs were similar to those of commonly prescribed ASMs, and no TEAEs leading to death were reported. Conclusions and Relevance: The efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs. Trial Registration: ClinicalTrials.gov Identifier: NCT03796962.

Clinical characteristics and treatment experience of individuals with SCN8A developmental and epileptic encephalopathy (SCN8A-DEE): Findings from an online caregiver survey.

PURPOSE: SCN8A developmental epileptic encephalopathy (SCN8A-DEE) is a rare and severe genetic epilepsy syndrome characterized by early-onset developmental delay, cognitive impairment, and intractable seizures. SCN8A gene variants are associated with a broad phenotypic spectrum and variable disease severity. A caregiver survey, solicited by the advocacy group The Cute Syndrome Foundation (TCSF), was conducted to gather information on the demographics/disease presentation, seizure history, and treatment of patients with SCN8A-related epilepsies. METHODS: A 36-question online survey was developed to obtain de-identified data from caregivers of children with SCN8A-related epilepsy. The survey included questions on genetic diagnosis, disease manifestations/comorbidities, seizure severity/type, current/prior use of antiseizure medicines (ASMs), and best/worst treatments per caregiver perception. RESULTS: In total, 116 survey responses (87 USA, 12 Canada, 12 UK, 5 Australia) were quantitatively analyzed. Generalized tonic/clonic was the most common seizure type at onset and time of survey; absence and partial/focal seizures were also common. Most patients (77%) were currently taking ≥2 ASMs; 50% had previously tried and stopped ≥4 ASMs. Sodium channel blockers (oxcarbazepine, phenytoin, lamotrigine) provided the best subjective seizure control and quality of life. CONCLUSION: The SCN8A-DEE patient population is heterogeneous in seizure characteristics and ASMs taken and is difficult to treat, with high seizure burden and multiple comorbidities. The high proportion of patients who previously tried and stopped ASMs indicates large unmet treatment need. Further collaboration between families, caregivers, patient advocates, clinicians, researchers, and industry can increase awareness and understanding of SCN8A-related epilepsies, improve clinical trial design, and potentially improve patient outcomes.

Effects of fremanezumab in patients with chronic migraine and comorbid depression: Subgroup analysis of the randomized HALO CM study.

OBJECTIVE: To evaluate the efficacy of fremanezumab in patients with chronic migraine (CM) and moderate to severe depression. BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, has been approved for the preventive treatment of migraine in adults. CM and depression are highly comorbid. METHODS: The 12-week, Phase 3 HALO trial randomized patients with CM to fremanezumab quarterly (675 mg/placebo/placebo), fremanezumab monthly (675/225/225 mg), or placebo. Post hoc analyses evaluated the effects of fremanezumab in patients with moderate to severe depression (baseline 9-item Patient Health Questionnaire sum score ≥10) on monthly number of headache days of at least moderate severity; monthly migraine days; Patient Global Impression of Change (PGIC); 6-item Headache Impact Test (HIT-6) scores; and depression. RESULTS: For the 219/1121 (19.5%) patients with moderate to severe depression at baseline, fremanezumab was associated with a significant reduction in monthly number of headache days of at least moderate severity for active treatment versus placebo (least-squares mean change ± standard error for quarterly dosing: -5.3 ± 0.77; for monthly dosing: -5.5 ± 0.72; and for placebo: -2.2 ± 0.81; both p < 0.001). More patients achieved a ≥50% reduction in headache days of at least moderate severity with fremanezumab (quarterly: 31/78 [39.7%]; monthly: 39/96 [40.6%]) than placebo (9/67 [13.4%]; both p < 0.001). Compared with placebo, fremanezumab improved PGIC and HIT-6 scores. CONCLUSIONS: Fremanezumab demonstrated efficacy in the preventive treatment of CM and reduced headache impact in patients with comorbid depression.

Capturing seizures in clinical trials of antiseizure medications for KCNQ2-DEE.

Literature review of patients with KCNQ2 developmental and epileptic encephalopathy (KCNQ2-DEE) reveals, based on 16 reports including 139 patients, a clinical phenotype that includes age- and disease-specific stereotyped seizures. The typical seizure type of KCNQ2-DEE, focal tonic, starts within 0-5 days of life and is readily captured by video-electroencephalography VEEG for clinical and genetic diagnosis. After initial identification, KCNQ2-DEE seizures are clinically apparent and can be clearly identified without the use of EEG or VEEG. Therefore, we propose that the 2019 recommendations from the International League against Epilepsy (ILAE), the Pediatric Epilepsy Research Consortium (PERC), for capturing and recording seizures for clinical trials (Epilepsia Open, 4, 2019, 537) are suitable for use in KCNQ2-DEE‒associated antiseizure medicine (ASM) treatment trials. The ILAE/PERC consensus guidance states that a caregiver-maintained seizure diary, completed by caregivers who are trained to recognize seizures using within-patient historical recordings, accurately captures seizures prospectively in a clinical trial. An alternative approach historically endorsed by the Food and Drug Administration (FDA) compares seizure counts captured on VEEG before and after treatment. A major advantage of the ILAE/PERC strategy is that it expands the numbers of eligible patients who meet inclusion criteria of clinical trials while maintaining accurate seizure counts (Epilepsia Open, 4, 2019, 537). Three recent phase 3 pivotal pediatric trials investigating ASMs to treat syndromic seizures in patients as young as 2 years of age (N Engl J Med, 17, 2017, 699; Lancet, 21, 2020, 2243; Lancet, 17, 2018, 1085); and ongoing phase 2 open-label pediatric clinical trial that includes pediatric epileptic syndromes as young as 1 month of age (Am J Med Genet A, 176, 2018, 773), have already used caregiver-maintained seizure diaries successfully. For determining the outcome of a KCNQ2-DEE ASM treatment trial, the use of a seizure diary to count seizures by trained observers is feasible because the seizures of KCNQ2-DEE are clinically apparent. This strategy is supported by successful precedent in clinical trials in similar age groups and has the endorsement of the international pediatric epilepsy community.

Effects of fremanezumab on the use of acute headache medication and associated symptoms of migraine in patients with episodic migraine.

BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody targeting calcitonin gene-related peptide, has demonstrated efficacy for the preventive treatment of migraine in adults. OBJECTIVE: To evaluate the effect of fremanezumab treatment on acute headache medication use and migraine-associated symptoms in patients with episodic migraine. METHODS: In the Phase 3 HALO trial, patients with episodic migraine were randomized to receive subcutaneous fremanezumab monthly (225 mg at baseline, weeks 4 and 8), fremanezumab quarterly (675 mg at baseline, placebo at weeks 4 and 8), or placebo over a 12-week period. The secondary endpoint was change from baseline in the monthly number of days with use of any acute headache mediation or migraine-specific acute headache medication; exploratory endpoints were change from baseline in the monthly number of days with nausea or vomiting, photophobia, or phonophobia. RESULTS: Of 875 patients randomized, 865 were included in the analysis (monthly, n = 287; quarterly, n = 288; placebo, n = 290). Baseline mean ± standard deviation days with: Any acute headache medication use (monthly: 7.7 ± 3.4; quarterly: 7.8 ± 3.7; placebo: 7.7 ± 3.6), migraine-specific acute headache medication use (6.1 ± 3.1; 6.6 ± 3.1; 7.1 ± 3.0), nausea or vomiting (4.5 ± 3.6; 4.9 ± 3.7; 4.5 ± 3.3) and photophobia and phonophobia (5.5 ± 4.1; 6.3 ± 4.1; 6.0 ± 3.9) were similar among treatment arms. Fremanezumab reduced the number of days of acute headache medication use ([least-squares mean change vs. placebo] monthly: -1.4 [95% confidence interval: -1.84, -0.89], p < 0.001; quarterly: -1.3 [-1.76, -0.82], p < 0.001) and migraine-specific acute headache medication use (monthly: -2.2 [-2.80, -1.56], p < 0.001; quarterly: -2.2 [-2.81, -1.58], p < 0.001) compared with placebo. Fremanezumab also reduced nausea or vomiting, photophobia, and phonophobia compared with placebo. CONCLUSIONS: Fremanezumab reduced the need for acute headache medications, including migraine-specific medications, while treating migraine-associated symptoms in patients with episodic migraine. TRIAL REGISTRATION: Clinicaltrials.gov NCT02629861.

Early Onset of Efficacy With Fremanezumab for the Preventive Treatment of Chronic Migraine.

OBJECTIVE: To assess the onset of efficacy for fremanezumab in chronic migraine by evaluating pain-related clinical measures at different time points. BACKGROUND: Faster onset of efficacy of preventive treatments could benefit patients with migraine. Fremanezumab is a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, a neuropeptide involved in the pathophysiology of migraine. In 12-week clinical trials, subcutaneous fremanezumab significantly reduced the frequency of migraine headaches, headache hours, and headaches in general, without serious treatment-related adverse events. New drug classes of migraine preventive treatment demonstrate markedly different clinical profiles from standard-of-care treatments. METHODS: In this double-blind phase III study, eligible patients were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly (675 mg at baseline, placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline, 225 mg at weeks 4 and 8), or placebo at each time point. This study included secondary, exploratory, and post hoc analyses of the primary trial, evaluating the change in headache days of at least moderate severity or migraine days during the first 4 weeks of the trial. RESULTS: A total of 1130 patients were randomized (fremanezumab quarterly, n = 376; fremanezumab monthly, n = 379; or placebo, n = 375). During the 4-week period after the first dose, the mean number of monthly headache days of at least moderate severity was reduced for the all-fremanezumab group (mean reduction [95% confidence interval]: -4.6 days [-5.1, -4.1]) compared with the placebo group (-2.3 days [-2.9, -1.6]; P < .0001). Treatment effects were observed at Week 1 for the all-fremanezumab group (-1.1 days [-1.3, -1.0]) vs placebo (-0.5 days [-0.7, -0.3]; P < .0001), with separation from placebo by Day 2 (P = .003). Similar effects were observed for the monthly average number of migraine days and mean number of monthly headache hours. CONCLUSIONS: The early onset of efficacy of fremanezumab may have the potential to improve patient compliance and clinical outcomes.

Safety and Tolerability of Fremanezumab for the Prevention of Migraine: A Pooled Analysis of Phases 2b and 3 Clinical Trials.

OBJECTIVE: Presentation of pooled analysis of safety data for fremanezumab in patients with chronic (CM) or episodic migraine (EM) from 4 placebo-controlled phase 2b and phase 3 studies. BACKGROUND: There is a need for an effective, safe, and well-tolerated preventive therapy that specifically targets the pathophysiology of migraine to reduce the frequency and severity of migraine attacks in patients with CM or EM who experience 4 or more migraine days per month. Fremanezumab is a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, a neuropeptide involved in the pathophysiology of migraine. DESIGN/METHODS: The 4 placebo-controlled phases 2b and 3 studies included in this analysis were 16-week, multicenter, randomized, double-blind, placebo-controlled, and parallel-group studies consisting of a screening visit, a 28-day pretreatment baseline period, and a 12-week treatment period with a final evaluation 4 weeks after the final dose of the study drug. Safety endpoints included adverse events (AEs) and immunogenicity. RESULTS: A total of 2566 patients were randomized across all studies (fremanezumab, n = 1704; placebo, n = 862), and 2563 patients were treated. Common reasons for study discontinuation were withdrawal by patient (n = 78), patient lost to follow-up (n = 60), and AE (n = 50). The mean (standard deviation) duration of exposure was 83.8 (13.6) days for the patients who received fremanezumab, with a total exposure of 390.4 patient years and maximum exposure of 181 days. AEs were mostly mild to moderate in severity and were reported among 48-69% of patients in all treatment groups, and most were injection site reactions (pain, induration, and erythema). Two deaths occurred (chronic obstructive pulmonary disease and intentional overdose of diphenhydramine), both of which were deemed unrelated to study drug by the investigators and sponsor. Cardiovascular adverse events, abnormal liver function tests, and hypersensitivity were uncommon and occurred at similar rates between the placebo and fremanezumab groups. CONCLUSIONS: Fremanezumab is a generally safe and well-tolerated preventive therapy for migraine in adults.

Sustained reductions in migraine days, moderate-to-severe headache days and days with acute medication use for HFEM and CM patients taking fremanezumab: Post-hoc analyses from phase 2 trials.

BACKGROUND: In phase 2 and 3 studies, fremanezumab, a monoclonal CGRP antibody, was an effective preventive treatment for high-frequency episodic migraine (HFEM) and chronic migraine (CM). OBJECTIVE: Post-hoc analyses evaluated population-wise 50%, 75% and 100% responder rates, and the extent to which individual responders sustained a 50%, 75% and 100% reduction in migraine days, moderate-to-severe (M/S) headache days and days of acute medication use during all three treatment months of the fremanezumab phase 2 studies. DESIGN/METHODS: HFEM patients received either placebo or three once-monthly injections of 225 mg or 675 mg. CM patients received either placebo or three once-monthly injections of 900 mg, or an initial loading dose of 675 mg and subsequent injections of 225 mg. Patients reported headache-related data daily using an electronic diary. RESULTS: In the HFEM study, the percent of patients on fremanezumab doses 225 mg and 675 mg were greater compared to the percent of placebo patients with sustained 50% reduction in migraine days (39% and 35% vs. 10% for placebo, both p < 0.0001), M/S headache days (36% and 38% vs. 16% placebo, p = 0.0017 and p = 0.0007 respectively), and acute medication use days (36% and 27% vs. 8% placebo, p < 0.0001 and p = 0.0003). Likewise, although there were fewer patients with sustained 75% reduction, there were increases in the percent of patients on fremanezumab 225 mg and 675 mg in the HFEM study relative to placebo patients in migraine days (19% and 11% vs. 3% placebo, p = 0.0002 and p = 0.0176), M/S headache days (19% and 15% vs. 2% placebo, p = 0.0001 and p = 0.0011) and days of acute medication use (16% and 8% vs. 2% placebo, p = 0.0005 and p = 0.0377). In the CM study, there were increases in the percent of patients on fremanezumab 675/225 mg and 900 mg with 50% sustained reduction in M/S headache days (32% and 40% vs. 15% placebo, p = 0.0058 and p = 0.0002) and days of acute medication use (26% and 22% vs. 11% placebo, p = 0.0098 and p = 0.0492). There were also increases in the percent of patients on fremanezumab 675/225 mg and 900 mg compared to patients on placebo with 75% sustained reduction in M/S headache days (10% and 13% vs. 3%, p = 0.0665 and p = 0.0203). Few patients had 100% sustained reductions in these parameters in either study. CONCLUSIONS: Post-hoc results must be interpreted with caution; nonetheless, a statistically significant percentage of patients who initially responded to fremanezumab within 1 month sustained this response over the subsequent 2 months. Sustained reduction in individual patients may provide a novel patient-centric, clinically meaningful endpoint for future trials assessing the effectiveness of preventive migraine treatments. Trials are registered as http://clinical trials.gov as NCT02025556 and NCT02021773.

The Effect of Beginning Treatment With Fremanezumab on Headache and Associated Symptoms in the Randomized Phase 2 Study of High Frequency Episodic Migraine: Post-Hoc Analyses on the First 3 Weeks of Treatment.

BACKGROUND: Migraine has a substantial impact on daily living, affecting productivity and quality of life for patients and their families. Patients frequently discontinue preventive medications in part because of a delay in headache and symptom relief due to the long dose titration procedures necessary for some migraine preventives. OBJECTIVE: To evaluate the efficacy of fremanezumab, a selective monoclonal CGRP ligand antibody, during the first 3 weeks of therapy in patients with high-frequency episodic migraine (HFEM) to relieve migraine headaches and associated symptoms and to reduce use of acute migraine medications. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, phase 2 study, patients with HFEM who met inclusion criteria and were 80% compliant with daily headache diary entry were randomized and treated once every 28 days for 3 months with either placebo or fremanezumab 225 or 675 mg. Compared to placebo, both doses of fremanezumab significantly reduced the primary endpoint of the HFEM study, change in the number of migraine days in month 3 relative to baseline. Herein, we performed post-hoc analyses to assess the efficacy of each dose during the first 3 weeks of treatment to reduce migraine headache parameters, associated migraine symptoms, and the consumption of acute migraine medications. RESULTS: The sample consisted of 297 study participants. Compared to placebo, decreases in migraine days were seen during the first week of therapy for both fremanezumab doses with least square mean (LSM) differences between fremanezumab 225 mg and placebo of -0.93 (95% CI: -1.36, -0.49) and between 675 mg dose and placebo of -1.02 (95% CI: -1.46, -0.58), both P < .0001. This benefit was maintained through the second week of therapy for the 225 and 675 mg doses, respectively, (-0.76 (95% CI: -1.11, -0.40) P < .0001, -.79 (95% CI: -1.15, -0.44) P < .0001) and the third week of therapy (-0.64 (95% CI: -0.97, -0.30) P = .0003 and -0.64 (95% CI: -0.98, -0.30) P = .0003). Likewise in the first week, patients recorded reductions in associated migraine symptoms such as nausea, vomiting, photophobia, and phonophobia, which continued through weeks 2 and 3. There were also reductions in days with acute medication use to treat migraine for the 225 and 675 mg fremanezumab doses compared to placebo. In the first week, LSM differences between 225 mg and placebo were -1.02 (95% CI: -1.39, -0.64) and between 675 mg and placebo were -1.06 (95% CI: -1.39, -0.64) P < .0001); for the second and third weeks (-1.01 (95% CI: -1.14, -0.55) P < .0001; -.90 (95% CI: -1.04, -0.44) P < .0001; -.91 (95% CI: -0.92, -0.34) P < .0001; and -.83 (95% CI: -0.84, -0.26) P = .0002), respectively. CONCLUSION: Fremanezumab treatment resulted in a rapid preventive response in patients with HFEM, with reductions seen in several headache parameters and migraine symptoms within the first week after therapy initiation and continuing during the second and third weeks. Patients also were able to rapidly reduce their use of acute medications to treat migraine attacks. The trial is registered at Clinicaltrials.gov as NCT02025556.

From LBR-101 to Fremanezumab for Migraine.

Calcitonin gene-related peptide (CGRP) is a neuropeptide of importance in migraine pathogenesis. Its central role in migraine was proven pharmacologically by the development of CGRP receptor antagonists. Monoclonal antibodies targeting CGRP or its receptor are effective in the preventive treatment of episodic and chronic migraine and are considered potential breakthroughs in their treatment. Fremanezumab (previously known as TEV-48125, LBR-101, or RN-307) is a humanized IgG2a monoclonal antibody that binds to CGRP. The development of this antibody validated the role of CGRP in chronic migraine and the drug has been recently approved in the US by the FDA, while it continues to be reviewed by other regulatory agencies. Herein we provide an in-depth review of its development. We start by summarizing its in vitro and in vivo pharmacology, and the phase I studies. We then review the late-stage clinical development, with a focus on its efficacy, safety, similarities, and uniqueness relative to other CGRP antibodies. We close by discussing lessons learned on the mechanisms of migraine and areas for future development and exploration.

Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine: A Randomized Clinical Trial.

Importance: Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine. Objective: To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose. Design and Setting: Randomized, double-blind, placebo-controlled, parallel-group trial conducted at 123 sites in 9 countries from March 23, 2016 (first patient randomized), to April 10, 2017, consisting of a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation at week 12. Participants: Study participants were aged 18 to 70 years with episodic migraine (6-14 headache days, with at least 4 migraine days, during 28-day pretreatment period). Patients who had previous treatment failure with 2 classes of migraine-preventive medication were excluded. Interventions: Patients were randomized 1:1:1 to receive subcutaneous monthly dosing of fremanezumab (n = 290; 225 mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675 mg of fremanezumab at baseline; placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8). Main Outcomes and Measures: The primary end point was mean change in mean number of monthly migraine days during the 12-week period after the first dose. Results: Among 875 patients who were randomized (mean age, 41.8 [SD, 12.1] years; 742 women [85%]), 791 (90.4%) completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 days to 4.9 days in the fremanezumab monthly dosing group, from 9.2 days to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference with monthly dosing vs placebo of -1.5 days (95% CI, -2.01 to -0.93 days; P < .001) and with single higher dosing vs placebo of -1.3 days (95% CI, -1.79 to -0.72 days; P < .001). The most common adverse events that led to discontinuation were injection site erythema (n = 3), injection site induration (n = 2), diarrhea (n = 2), anxiety (n = 2), and depression (n = 2). Conclusions and Relevance: Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3- to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy. Trial Registration: clinicaltrials.gov Identifier: NCT02629861.

A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects.

OBJECTIVES: The primary and secondary objectives of this phase 1 study were to evaluate the pharmacokinetic profile, safety, and immunogenicity of fremanezumab subcutaneous (sc) doses tested in phase 2 and 3 trials (225 mg, 675 mg and 900 mg) following single administration in Japanese (n = 32) and Caucasian (n = 32) healthy subjects. METHODS: Japanese and matched Caucasian healthy subjects were enrolled into one of four cohorts and were randomly assigned to one of four treatments: 225, 675, or 900 mg fremanezumab, or placebo. Pharmacokinetic and immunogenicity sampling, and safety and tolerability assessments occurred at one inpatient visit and 12 ambulatory visits during the 36-week study. RESULTS: Pharmacokinetic analyses included those randomized to fremanezumab (n = 24 for each ethnic group) and safety analyses included all subjects enrolled in the study (n = 32 for each ethnic group). Fremanezumab concentration-time profiles and pharmacokinetic parameters per dose were similar for Japanese and Caucasians at all dose levels. Geometric mean ratios (GMRs) for Cmax for Japanese to Caucasian subjects were 0.91, 1.04 and 1.14 for the 225 mg, 675 mg and 900 mg fremanezumab doses. GMRs for AUC0-inf were 0.96, 1.09, and 0.98, respectively. Median Tmax (range 5-11 days) and mean half-lives (range 31-39 days) were similar across doses for both ethnicities. Most frequently occurring adverse events were injection site reactions, abdominal pain, headache, upper respiratory tract infection, constipation and nasopharyngitis. There was no development of anti-drug-antibodies and no clinically meaningful changes in laboratory findings. CONCLUSION: The results of the pharmacokinetic exposure parameters and safety measures were similar for Japanese and Caucasians and support the once monthly and once quarterly sc injections of fremanezumab.

Fremanezumab for the Preventive Treatment of Chronic Migraine.

BACKGROUND: Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being investigated as a preventive treatment for migraine. We compared two fremanezumab dose regimens with placebo for the prevention of chronic migraine. METHODS: In this phase 3 trial, we randomly assigned patients with chronic migraine (defined as headache of any duration or severity on ≥15 days per month and migraine on ≥8 days per month) in a 1:1:1 ratio to receive fremanezumab quarterly (a single dose of 675 mg at baseline and placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), or matching placebo. Both fremanezumab and placebo were administered by means of subcutaneous injection. The primary end point was the mean change from baseline in the average number of headache days (defined as days in which headache pain lasted ≥4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine-specific medication [triptans or ergots] was used to treat a headache of any severity or duration) per month during the 12 weeks after the first dose. RESULTS: Of 1130 patients enrolled, 376 were randomly assigned to fremanezumab quarterly, 379 to fremanezumab monthly, and 375 to placebo. The mean number of baseline headache days (as defined above) per month was 13.2, 12.8, and 13.3, respectively. The least-squares mean (±SE) reduction in the average number of headache days per month was 4.3±0.3 with fremanezumab quarterly, 4.6±0.3 with fremanezumab monthly, and 2.5±0.3 with placebo (P<0.001 for both comparisons with placebo). The percentage of patients with a reduction of at least 50% in the average number of headache days per month was 38% in the fremanezumab-quarterly group, 41% in the fremanezumab-monthly group, and 18% in the placebo group (P<0.001 for both comparisons with placebo). Abnormalities of hepatic function occurred in 5 patients in each fremanezumab group (1%) and 3 patients in the placebo group (<1%). CONCLUSIONS: Fremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo in this 12-week trial. Injection-site reactions to the drug were common. The long-term durability and safety of fremanezumab require further study. (Funded by Teva Pharmaceuticals; ClinicalTrials.gov number, NCT02621931 .).

Fremanezumab as Add-On Treatment for Patients Treated With Other Migraine Preventive Medicines.

BACKGROUND: Fremanezumab (formerly TEV-48125) is a monoclonal antibody directed against calcitonin-gene-related peptide (CGRP), a validated target for migraine preventive therapy. In two previous phase 2 studies, fremanezumab administered once every 28 days for 12 weeks was found to be effective and safe as a preventive treatment for patients suffering from episodic migraine (EM) and chronic migraine (CM). OBJECTIVE: To evaluate the efficacy and safety of fremanezumab as an add-on preventive therapy in individuals with EM and CM who are on stable doses of preventive migraine medications. METHODS: Two randomized placebo-controlled studies tested once-monthly subcutaneous injections of various dosing regimens of fremanezumab versus placebo in EM and CM. Headache information was captured daily using an electronic headache diary. For these post hoc analyses, data were pooled from patients who were on stable preventive medications and taking fremanezumab doses of 225 mg or 675/225 mg, or placebo. RESULTS: The sample consisted of 133 patients, (67 fremanezumab and 66 placebo). Total reduction in migraine days for the duration of the study was 12.4 for fremanezumab and 7.4 for placebo (P = .0321). There were also decreases in moderate/severe headache days (12.5 vs 7.1, P = .0058), and days using acute medication for headaches relative to placebo (11.6 vs 7.5, P = .0414). Treatment emergent adverse events were generally mild and transient, and no serious adverse events were considered to be treatment-related by the site investigators. CONCLUSIONS: The findings from these post hoc analyses suggest that fremanezumab is a safe and effective add-on treatment for migraine patients being concomitantly treated with other migraine preventive medications. Trials are registered at Clinicaltrials.gov NCT02025556 and NCT02021773.

Humanistic and economic burden of nausea and vomiting among migraine sufferers.

BACKGROUND: While studies have demonstrated the economic burden of migraines in terms of quality of life, health care resource use (HRU), and costs, there exists a notable paucity of data comparing such outcomes among migraineurs with nausea and vomiting (N/V) and those without. The current study aimed to address this gap. METHODS: This was a retrospective study using data from the 2013 US National Health and Wellness Survey, a cross-sectional, internet-based survey. Respondents self-reported their migraine with or without N/V along with demographics and outcomes including depression (Patient Health Questionnaire total score; PHQ-9), sleep problems (11-item total score of sleep problems), HRU (number of physician visits, emergency room [ER] visits, and hospitalizations) and Work Productivity and Activity Impairment-General Health Scale (WPAI-GH), and associated mean annual costs. Generalized linear models, adjusting for covariates, assessed the burden of N/V on all outcomes. RESULTS: Among all migraineurs (N=7,855), 73.4% were female, mean age was 41.82 years old, and 57.6% reported experiencing N/V. Adjusting for covariates, migraineurs with N/V vs without N/V had higher mean PHQ-9 scores (7.91 vs 7.02, p<0.001) and mean sleep problems (3.29 vs 2.64, p<0.001). Mean ER visits were more frequent among migraineurs with N/V than those without N/V (0.48 vs 0.38, p=0.001). This difference translated into a 26.3% increase in estimated mean ER costs (N/V=US$1,499 vs without N/V=US$1,187, p=0.002). Mean percentage activity impairment was higher in migraineurs with N/V than in those without N/V (37.73% vs 35.12%, p=0.002) and migraineurs with N/V had higher work productivity loss costs (N/V=US$10,344 vs without N/V=US$9,218, p=0.016). CONCLUSION: Migraine patients with N/V reported worse depression, sleep problems, and activity impairment, and higher ER visits than those without N/V. Migraine with N/V was also associated with an increase in mean annual ER visit costs and work productivity loss costs. Study findings suggest unmet needs with current treatment options for migraine patients with N/V.

A Phase I, Open-Label, Single-Dose Safety, Pharmacokinetic, and Tolerability Study of the Sumatriptan Iontophoretic Transdermal System in Adolescent Migraine Patients.

OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetics of sumatriptan delivered by the iontophoretic transdermal system (TDS) in adolescent patients. BACKGROUND: Since nausea can be a prominent and early symptom of migraine, nonoral treatment options are often required. Sumatriptan iontophoretic TDS is approved for the acute treatment of migraine in adults. The present study evaluates the pharmacokinetics of sumatriptan administered via the iontophoretic TDS in adolescents, contrasting the findings with historical data from adults. DESIGN: Patients aged 12-17 years (inclusive) with acute migraine were treated with sumatriptan iontophoretic TDS for 4 hours. Blood samples for pharmacokinetic profiling of sumatriptan were obtained prior to dosing and at predetermined time points covering the 12 hours postonset of treatment. Key pharmacokinetic endpoints included Cmax (peak plasma drug concentration), tmax (time to Cmax ), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and t½ (terminal elimination half-life). Safety was evaluated by monitoring of adverse events in addition to laboratory and clinical assessments. RESULTS: The sample consisted of 37 patients, and 36 were included in the PK evaluable population. Cmax , tmax , AUC0-∞ , and t½ values were all similar between male and female patients and between younger (12-14 years) and older (15-17 years) adolescents. When compared with historical adult data, adolescent patients demonstrated similar systemic exposures to those observed in adults (mean Cmax 20.20 (±6.43) ng/mL in adolescents vs 21.89 (±6.15) ng/mL in adults; mean AUC0-∞ 98.1 (±28.1) ng·h/mL in adolescents vs 109.7 (±26.1) ng·h/mL in adults). All adverse events were mild or moderate, with application-site paresthesia being the most common (32%). No clinically relevant changes in laboratory values, vital signs, or electrocardiogram findings were observed. CONCLUSIONS: The iontophoretic TDS produced mean systemic exposures to sumatriptan in younger and older adolescents, in line with what was seen in adult subjects. It was generally well tolerated.

TEV-48125 for the preventive treatment of chronic migraine: Efficacy at early time points.

OBJECTIVE: To evaluate the onset of efficacy of TEV-48125, a monoclonal antibody against calcitonin gene-related peptide, recently shown to be effective for the preventive treatment of chronic migraine (CM) and high-frequency episodic migraine. METHODS: A randomized placebo-controlled study tested once-monthly injections of TEV-48125 675/225 mg or 900 mg vs placebo. Headache information was captured daily using an electronic headache diary. The primary endpoint was change from baseline in the number of headache hours in month 3. Herein, we assess the efficacy of each dose at earlier time points. RESULTS: The sample consisted of 261 patients. For headache hours, the 675/225-mg dose separated from placebo on day 7 and the 900-mg dose separated from placebo after 3 days of therapy (p = 0.048 and p = 0.033, respectively). For both the 675/225-mg and 900-mg doses, the improvement was sustained through the second (p = 0.004 and p < 0.001) and third (p = 0.025 and p < 0.001) weeks of therapy and throughout the study (month 3, p = 0.0386 and p = 0.0057). For change in weekly headache days of at least moderate intensity, both doses were superior to placebo at week 2 (p = 0.031 and p = 0.005). CONCLUSIONS: TEV-48125 demonstrated a significant improvement within 1 week of therapy initiation in patients with CM. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with CM, TEV-48125 significantly decreases the number of headache hours within 3 to 7 days of injection.

Pharmacokinetics and pharmacodynamics of multiple doses of BG00010, a neurotrophic factor with anti-hyperalgesic effects, in patients with sciatica.

AIMS: BG00010 is a protein in the glial cell line-derived neurotrophic factor (GDNF) family. It is a selective ligand for the GDNF family receptor alpha-3 (GFRα3) co-receptor that normalizes cellular changes resulting from damage or disease, and potentially alleviates neuropathic pain. The main objectives of this study were to evaluate the pharmacokinetic and safety profiles and to determine the effects on pain of ascending doses of intravenous injections of BG00010 in patients with sciatica. METHODS: This was a randomized, blinded, placebo-controlled multiple-dose study in subjects with sciatica. In Part I (16 patients), four IV dose levels were examined (50, 150, 400, 800 µg kg(-1) ) and in Part II (12 patients), three dose levels were examined (400, 600 and 1200 µg kg(-1) ). Safety and efficacy assessments were used as endpoints. RESULTS: The BG00010 concentration-time data indicated relatively low inter-patient variability and there was a dose-dependent (not dose-proportional) increase in serum exposure from 150 to 1200 µg kg(-1) . The effective half-life was between 40 and 60 h. The most frequently occurring adverse events (AEs) reported by patients receiving BG00010 were headache (67-83%), feeling hot (50-100%), and pruritus (42-67%). Most AEs were mild; no serious AEs or AEs leading to discontinuation occurred. Higher dose regimens of BG00010 resulted in greater pain reduction than placebo or lower dose regimens, although a clear dose-response relationship was not seen. CONCLUSIONS: The pharmacokinetic profile of BG00010 was characterized by low intra-patient variability. These data from a small sample suggest that BG00010 may have a benefit for patients with sciatica.

Subcutaneous interferon ß-1a in pediatric patients with multiple sclerosis: Regional differences in clinical features, disease management, and treatment outcomes in an international retrospective study.

BACKGROUND: To further understand management of pediatric patients with multiple sclerosis (MS), we examined disease features, clinical practice patterns, and response to treatment in the United States (US) and seven other countries ('rest of World'; ROW). METHODS: Anonymized data, recorded as part of routine clinical practice, were obtained from medical records (1997-2009) of study participants (who received subcutaneous interferon ß-1a before age 18 years) from the US and ROW. Samples were stratified by age (preadolescents [<12 years] and adolescents [12-17 years]). RESULTS: US adolescents had a higher mean body mass index versus ROW adolescents (BMI; 27.2 versus 22.5 kg/m(2)), started disease-modifying therapy (DMT) earlier after the first relapse, were more likely to have received a DMT before initiating subcutaneous interferon ß-1a, had a higher relapse rate, and were more likely to switch from subcutaneous interferon ß-1a to another DMT before the end of the observation period. CONCLUSIONS: This retrospective analysis of a multinational sample of pediatric MS patients who received subcutaneous interferon ß-1a found that those from the US had higher BMI, relapsed more frequently, and were managed differently, compared with ROW patients. Future prospective studies are needed to confirm these observations and ascertain their clinical significance.